pathogens have evolved ingenious strategies to circumvent the host immune response as part of the constant evolutionary process - taking place in all living organisms . chief among these strategies is the prevention of the inflammatory response or seizure of the anti - inflammatory mechanism in place to protect tissue integrity . the manipulation of macrophage ( m ) polarization is one of the main targets to accomplish this , since this antigen presenting cell represents the first line of an active defense system in the host , and if successfully done , it can then undermine adaptive immunity ( benoit et al . , 2008 ) . m polarization is a dynamic process governed by mechanisms dictating their tissue distribution and functional capacities in response to endogenous and exogenous signals ( martinez et al . , 2009 ) . polarized ms are broadly classified into two groups : classical ( m1 ) and alternative ( m2 ) activated . on one hand , m1 program is a direct response to type-1 inflammatory conditions ( e.g. , ifn- ) and pathogen challenge , and it has been associated to resistance to intracellular pathogens and to some form of tumors . on the other hand , the m2 program is driven by type-2 inflammatory signals such as il-4 and il-13 ( m2a ) ; immune complexes , toll - like receptors ( tlrs ) agonists , or il-1 receptors ( m2b ) ; and immunosuppressants including il-10 , transforming growth factor- ( tgf- ) or glucocorticoids ( m2c ; table 1 ) . m2 ms participate in diverse activities including the suppression of inflammation , enhancement of phagocytosis , promotion of tissue remodeling and repair , elimination of parasites , and unwanted tumor angiogenesis ( sica et al . , 2008 ; martinez et al . furthermore , it is becoming clear that m polarization supports different , and in some cases , opposing biological functions , that influences tissue homeostasis , and numerous pathological situations , including infectious diseases ( benoit et al . given the pivotal role ms play as sentinels of the immune system , they represent ideal cell targets for subversion by successful intracellular pathogens . priming stimulus for the classical ( m1 ) and alternative ( m2a - c ) activation of macrophages . the purpose of this short review is not to provide a comprehensive summary of m polarization ; others have recently reviewed this growing research area ( martinez et al . also , we will not address the multiple ways by which the pathogens in question circumvent the immune system , as there are excellent reviews covering this subject ( deretic et al . , 2004 ; carter and ehrlich , 2008 ; meena and rajni , 2010 ; hajishengallis and lambris , 2011 ) . instead , we will focus exclusively on the significance of m polarization in the context of pathophysiology caused by mycobacterium tuberculosis ( mtb ) and human immunodeficiency virus ( hiv ) . the world health organization reports tuberculosis ( tb ) is still one of the leading causes of death due to a single infectious agent ( mtb ) with 1.7 million deaths and 9.4 million new cases in 2009 , and estimates that about one - third of the human population may be latently infected ( who global tuberculosis control report 2010 , 2010 ) . active tb may occur directly after infection or through the reactivation of latent infection that is confined in granulomas . the elaboration and maintenance of granulomas depends on a dedicated immune response , which is not fully understood . recently , however , it was demonstrated mycobacteria exploits m activation to turn the granuloma into an effective tool for pathogenesis ( davis and ramakrishnan , 2009 ; volkman et al . , 2010 ) . therefore , a better understanding of m polarization during mtb infection might yield further clues about how mtb circumvents the immune system . as aforementioned , m polarization is mainly driven by type-1 and type-2 inflammatory signals ( table 1 ) . type-1 inflammatory cytokines are essential in the defense against mtb since their expression often correlates with efficient anti - mtb immune responses , and genetic deficiencies of these factors lead to increased tb susceptibility ( quintana - murci et al . , 2007 ) . ifn- drives the m1 program characterized by m capacity to kill most mycobacteria and restrict the replication of the remainder ( ehrt et al . , 2001 ) . the early phase of the anti - mtb immune response is marked by m1 m polarization in multiple animal models and reminiscent of the clinical data collected from patients with active tb ( figure 1 ; benoit et al . , 2008 ) . at the transcriptome level , the gene modulation induced by mtb in ms highly overlaps , and in some cases synergizes , with that induced by ifn- to establish the m1 phenotype ( ehrt et al . m1 m polarization is evident in mice between 7 and 30  days after mtb infection when high levels of ifn- and inos are also detected within this structure and around the alveolar compartment ( redente et al . , 2010 ) . all in all , polarization of m1 ms is part of the  common host response  against intracellular bacteria characterized by high expression of inos and consequent nitric oxide ( no ) production ( characteristic of murine models ) , secretion of pro - inflammatory cytokines and chemokines , release of proteolytic enzymes and anti - microbial peptides , enhanced phagocytosis , and development of a toxic intracellular environment reflected in the fusion of microbial phagosomes with acidic and hydrolase - rich lysosomes ( ehrt et al . , 2001 ; deretic et al . , 2004 ; martinez et al . , 2009 ; cairo et al . , 2011 ; murray and wynn , 2011 ) . it remains to be demonstrated whether transcription factors [ e.g. , p65 and interferon regulatory factor ( irf5 ) ] or regulators ( e.g. , ship1 ) that dictate the m1 program of macrophage polarization also play a role in tb infection ( martinez , 2011 ) . considering this hostile environment created by m1 ms , it is not surprising mtb has evolved strategies to interfere with m1 polarization . indeed , mtb inhibits ifn- activation of ms by secreting virulence factors such as lipoarabinomannan that halters phagosome maturation , or early secretory antigenic target-6 ( esat-6 ) that prevents the activation of nf-b and ifn- regulatory factors downstream of tlr-2 ( deretic et al . , 2004 ; benoit et al . , 2008 ) . indirectly , mtb blocks m1 polarization by the transcriptional inhibition of ifn--responsive genes through a bystander effect involving il-6 ( sibley et al . , 1990 ; benoit et al . , 2008 ) . a model illustrating the putative involvement of macrophage polarization during mtb or hiv-1 infection . perhaps the best strategy to avoid the challenges posed by m1 ms is to shift their program into m2 ms . tb susceptibility parallels with elevated levels of type-2 inflammatory signals ( e.g. , il-4 , il-13 ; kahnert et al . , 2006 ; raju et al . , 2008 ; almeida et al . , 2009 ; schreiber et al . , likewise , high levels of il-10 ( mostly derived from ms ) correlate with active tb patients ( barnes et al . , 1993 ; verbon et al . , 1999 interestingly , the predominant type-2 inflammatory environment shifts back to type-1 after successful treatment of pulmonary tb in infected patients ( verbon et al . , 1999 ; 2008 ) . these observations in humans parallel with those reported in mtb - infected mice ; that is , there is an early type-1 immune response characterized by ifn- during the first 3  weeks after infection , followed by a type-2 immune response that contains high levels of il-4 ( figure 1 ; orme et al . , 1993 ) . a type-2 inflammatory environment drives the m2 program that renders ms immunomodulatory and poorly microbicidal ( raju et al . , 2008 ; , this seems to be the case in mice since m2 ms displayed a diminished inflammatory response to mtb as reflected by a reduced no production and increased of iron availability , suggesting these phagocytes offer a permissible intracellular environment for bacterial replication ( kahnert et al . , 2006 ) . indeed , ifn--induced no production is essential for host survival with respect of experimental tb , while iron - starvation is key to bacteriostasis ( ehrt et al . , 2001 ; forbes and gros , 2001 ; cairo et al . , 2011 ) . it remains to be seen if mtb also influences the expression level of kruppel - like factor 4 ( klf4 ) or any other transcription factor / regulator recently shown to be critical for both the establishment of the m2 program and the inhibition of m1 polarization ( e.g. , stat6 , cot / tpl2 ; liao et al . , it has been demonstrated that both il-4 and il-13 inhibit autophagy in m1 ms resulting in enhanced survival of mtb , an impairment that might also extend to m2a ms ( harris et al . , 2007 ) . at the granuloma level in mice , inos continues to be expressed within this structure but a significant shift from m1 toward m2 ms [ inos arginase-1 ( arg1 ) ] occurs around the alveolar compartment starting at day 35 and continuing up to day 60 after mtb infection , accompanied by high levels of type-2 inflammatory signals ( ly et al . 2010 ) . given the development of fibrosis is a key characteristic of caseous granulomas during mtb dissemination , and that m2 ms have been implicated in the inhibition of fibrosis development , the shift from m1 into m2 program might represent an attempt by the host to halter the pathophysiology caused by mtb or a microbial strategy to shield from immune attack ( dorhoi et al . , 2011 ) . for instance , mtb might influence all tlr - dependent signaling by targeting dc - sign to induce il-10 and counteract the pro - inflammatory response , as shown in dendritic cells ( geijtenbeek et al . likewise , the mannosylated lipoarabinomannan from mtb enhances the production of il-10 and other immunosuppressants through recognition by the mannose receptor ( mr ) in immature dendritic cells ( chieppa et al . , 2003 ) . although alveolar ms express dc - sign and mr , their role in m2 ms has yet to be demonstrated ( chroneos and shepherd , 1995 ; tailleux et al . , 2005 ) ( 2009 ) reported mtb - induced il-10 in ms promotes the m2 polarization program displaying diminished anti - mycobacterial effector mechanisms . indeed , m - specific overexpressing il-10 transgenic mice were indeed susceptible to mtb infection , displayed a specifically suppressed il-12 in infected tissues , and were characterized by lung ms with a m2 phenotype permissive to mtb infection ( schreiber et al . , 2009 ) . these observations correlate well with another study in mice where mtb was shown to promote its survival and ability to cause disease through a myd88-dependent induction of arg1 . arg1 inhibits no production by ms by competing with inos for arginine ( the common substrate ) , thus rendering these cells permissive to mtb infection ( el kasmi et al . , 2008 ; hajishengallis and lambris , 2011 ) . taken together , these observations suggest the reprogramming toward m2 ms by il-10 , and other immunosuppressants such tgf- and glucocorticoids ( hernandez - pando et al . , 2006 ) , might be yet another adaptation by mtb to survive and thrive inside of ms ( figure 1 ) . however , it should be noticed that this phenomenon might also represent a control mechanism by the host to preserve the integrity of mucosal sites as uncontrolled type-1 inflammatory responses against mtb result into lung immunopathology ( hernandez - pando et al . , 2006 ; human immunodeficiency virus-1 is another successful intracellular pathogen responsible for a worldwide pandemic . according to 2009 estimates by the united nations , there were about 33.2 million people worldwide living with hiv-1 infection and 2.6 million individuals had been newly infected ( cohen et al . , 2011 ) . in the absence of antiviral therapy , hiv-1 infection progresses through acute and asymptomatic stages leading to the eventual failure of the host immunological functions and acquired immunodeficiency syndrome ( aids ) . a reason is that hiv-1 targets cells from the mononuclear phagocyte lineage that drive an effective antiviral response and simultaneously serve as reservoirs of latent or productive infection ( goodenow et al . , 2003 ) . among these cells , ms are critical to pathogenesis because they contribute to early transmission , systemic dissemination , and persistence of hiv-1 . indeed , hiv-1 evades immune surveillance by hiding and thriving inside ms despite anti - retroviral treatment , and when infected , they persist for months displaying insensitivity to viral cytopathic effects . in addition , ms continuously secrete high level of viral particles over prolonged time periods by storing assembled virus in specialized endosomal compartments ( orenstein et al . , 1988 ; benaroch et al . , thus , they represent powerful long - term viral reservoirs ( goodenow et al . , 2003 ; carter and ehrlich , 2008 ; herbein and varin , 2010 ; cohen et al . , 2011 ) . in light of recent evidence suggesting that m1 and m2 ms influence hiv-1 pathogenesis , there is a surging interest to study the viral effects in m polarization . in vitro , this m response includes production of type-1 pro - inflammatory cytokines ( ifn- , il-2 , il-12 , tnf , il-1 , il-6 , il-18 ) and chemokines ( ccl3 , ccl4 , mip- , mip- , rantes ) , increased no and respiratory burst , up - regulation of mhc - ii molecules , and down - regulation of hiv - entry receptors ( e.g. , cd4 , ccr5 , cxcr4 ) , and endocytic receptors ( e.g. , cd163 , cd206 ; swingler et al . , 1999 ; cassol et al . , 2009 , 2010 ; herbein and varin , 2010 ) . although few studies have examined thoroughly hiv - induced polarization of ms in vivo , there is a predominance of ms displaying a m1 phenotype during the acute stage ( figure 1 ; cassol et al . , 2010 ; herbein and varin , 2010 ; cohen et al . , 2011 ) . whether m1 ms are beneficial to the host during hiv-1 infection remains an open question since m functions vary according to the experimental context . for instance , in vitro infection of m1 ms in the presence of ifn- and tnf is associated with a suppression of hiv-1 replication , a sharp decrease in hiv-1 dna synthesis at 48  h , and a decrease in the accumulation of hiv-1 proteins ( cassol et al . , 2009 ) . in addition , other studies demonstrate that m1 ms inhibit viral entry , assembly , and budding , suggesting the m1 program can be beneficial to the host ( cassol et al . , 2010 ; herbein and varin , 2010 ) . however , it is also known that pro - inflammatory signals deriving from m1 ms favor the formation of viral reservoirs with increased transcription of hiv-1 ltr ( long terminal repeat ) , alluding m1 ms might benefit hiv pathogenesis ( cassol et al . , 2010 ; herbein and varin , 2010 ) . this is supported by multiple observations that immune activation driven by ms correlates with hiv-1 pathogenesis ( goodenow et al . , 2003 ; lamers et al . , 2009 ; cohen et al . , 2011 m1hiv  since it displays a pro - inflammatory state with increased production of cytokines independently of tlr - pathway . the authors argue that while hiv-1 stimulates ms through a variety of signaling pathways to promote a  tailored  inflammation in its favor , the tlr recognition of viral replication is impaired and could serve as a viral evasion strategy . given that prolonged pro - inflammatory m activation during chronic hiv - infection contributes , not only to a permissive environment for the formation of viral reservoirs with strong transcriptional activity , but also to disease progression and hiv - induced tissue damage , the proposed m1hiv polarized state may render ms detrimental to the host ( goodenow et al . , 2003 ; brown et al . , 2008 ; lamers et al . , 2009 ) . as hiv - disease progresses from the acute to asymptomatic stage , there is a switch from a type-1 toward a type-2 inflammatory environment ( figure 1 ; vasilescu et al . , 2003 ; becker , 2004 ) . at the transcriptional level , lymphatic tissue microarray analyses from hiv-1-infected subjects at different clinical stages revealed that each stage has a unique gene profile ( li et al . , 2009 ) . the asymptotic phase , however , down - regulates the acute phase gene profile to baseline level while it displays an increased expression of immunosuppressive genes ( li et al . , 2009 ) . based on these immunological systemic changes , it is likely that a polarization switch occurs in ms from a m1 program during the acute phase to the m2 programs through later stages . although there is no overwhelming evidence confirming the abundance of m2 ms in either the asymptotic or aids phase in vivo , the fact cd163 ( a m2 m cell surface marker ) is considered as a potential biomarker for hiv-1 disease progression may allude to the presence of m2 ms in hiv-1-infected individuals ( burdo et al . , 2011 ; tippett et al . , similar to m1 ms , it is not known whether m2 ms benefits the host during hiv-1 infection . in vitro activation of m2a ( il-4-treated ) ms results in inhibition of virus replication ( cassol et al . , 2009 ) . other studies have demonstrated that both il-4 and il-13 down - regulate viral entry receptors and hiv-1 reverse transcription in ms ( cassol et al . , 2010 ) . furthermore , activation of m2c ( il-10-treated ) ms strongly inhibits reverse transcription , transcription of hiv-1 ltr and viral assembly ( herbein and varin , 2010 ) . based on these observations , it might be tempting to conclude that m2 ms are beneficial to host immunity against hiv . however , the progression of aids is characterized by the loss of il-2 and increase of il-10 correlating with hiv viremia ( brockman et al . . moreover , the haplotypes of both il-4 and il-10 genes have been associated recently with aids progression ( vasilescu et al . , therefore , the switch toward a m2 m program might simply be part of a defensive mechanism by the host to control hiv - induced tissue damage since they participate in suppression of inflammation and promotion of tissue repair ( figure 1 ; martinez et al . recently , a functional proteomic analysis of hiv - infected ms in the presence of regulatory t cells showed that a deviation of m1 to m2 m program is associated with neuroprotection in the case of hiv - associated neurocognitive disorders , suggesting m2 ms may curtail the m1hiv polarized activity resulting in tissue damage ( huang et al . , 2010 ) . conversely , the switch toward the m2 m program might also occur as an evasion strategy by hiv to promote its own survival . a recent study demonstrated that hiv up - regulates both programmed cell death ligand 1 ( pd - l1 ) and pd - l2 expression , members of the b7:cd28 family , and pd-1 ligands , in ms ( porichis et al . , 2011 ) . given the importance of these molecules in t cell exhaustion during hiv infection , the ability of il-10 to both activate the m2c m program and induce pd - l1 , and the fact that il-10 production and increased expression of pd - l1 correlate in hiv - infected patients , the authors propose the manipulation of pdl expression in ms as a strategy to evade immune responses ( trabattoni et al . whatever the true role of m2 ms in hiv infection , it is clear they influence the establishment of hiv pathogenesis , and more studies are needed to examine thoroughly hiv - induced polarization of ms in vivo . tuberculosis is the most common opportunistic infection in aids and often used as a clinical parameter for undiagnosed aids cases ( deretic et al . , 2004 ) . while the synergy between mtb and hiv is evident at the clinical level , the mechanisms accounting for it are poorly understood . 2004 ) proposed the interference with endosomal sorting machine as a molecular mechanism contributing to the synergy between these two pathogens . likewise , we envision the pathogenic modulation of m polarization as a cellular mechanism that might influence this synergism . as aforementioned , it is estimated that about one - third of the human population may be latently infected with mtb ( who global tuberculosis control report 2010 , 2010 ) , suggesting that one in three of the 2.6 million people newly infected with hiv-1 in 2009 ( cohen et al . , 2011 ) latent mtb is confined in solid granulomas composed of mainly by ms and t cells that maintain their stability . the coinfection with hiv-1 results in a dramatic increase in the odds of latently infected people progressing into overt tb to a staggering annual risk of 10% ( deretic et al . , 2004 ; swaminathan et al . , hiv - driven immune perturbation , reflected in the loss of cd4 t cells and abnormal low levels of tnf causes the loss of granuloma integrity and efficiency in anti - microbial containment leading to post - primary reactivation state ( paige and bishai , 2010 ) . these events may increase both m necrosis and release of intracellular bacilli accounting for the extrapulmonary tb manifestation diagnosed in patients with hiv - driven immunosuppression ( swaminathan et al . the awakened mtb then might induce m1 ms to drive an excessive tnf response ( together with other mechanisms such as mmp secretion ) to deliberately promote parasitic granuloma formation , resulting in the recruitment of additional nave ms and the tissue pathology ( davis and ramakrishnan , 2009 ; paige and bishai , 2010 ; volkman et al . , 2010 ) . excessive levels of tnf , may not only contribute to the classical symptoms of cachexia in tb , but also to the augmentation of hiv-1 transcription and accelerated formation of viral reservoirs ( deretic et al . in the absence of an efficient adaptive immune response due to hiv - driven impairment , uncontrolled inflammation can result in lung immunopathology , and consequently , the host may induce tissue repair responses . the shift from m1 to m2 m program may become pronounced and prolonged in the sterile attempt to restore tissue integrity , elevating the level of il-10 that is typical of disease progression by both pathogens , and thus contributing to the failure of all immunological functions and clinical collapse . while highly speculative , this scenario highlights the importance to understand m polarization in the context of immune activation and pathogen - driven disease , and its potential to be yet another convergence point targeted by mtb and hiv to circumvent the host immune system . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
in the arms race of host  microbe co - evolution , macrophages ( ms ) have been endowed with strategies to neutralize pathogenic challenge while preserving host integrity . during steady - states conditions , 
 ms perform multiple house - keeping functions governed by their differentiation state , tissue distribution , and signals from the microenvironment . in response to pathogenic challenge and host mediators , 
 however , ms undergo different programs of activation rendering them either pro - inflammatory and microbicidal ( m1 ) , or immunosuppressants and tissue repairers ( m2 ) . 
 an excessive or prolonged polarization of either program may be detrimental to the host due to potential tissue injury or contribution to pathogenesis . 
 conversely , intracellular microbes that cause chronic diseases such as tuberculosis and acquired immunodeficiency syndrome exemplify strategies for survival in the host . 
 indeed , both mycobacterium tuberculosis ( mtb ) and human immunodeficiency virus ( hiv-1 ) are successful intracellular microbes that thrive in ms . given these microbes not only co - circulate throughout the developing world but each has contributed to prevalence and mortality caused by the other , substantial insights into microbe physiology and host defenses then rest in the attempt to fully understand their influence on m polarization . 
 this review addresses the role of m polarization in the immune response to , and pathogenesis of , mtb and hiv .