Editorial: Strangers with candy: policing the lungs with C‐type lectins

The lung is continuously exposed to inflammatory particles as a result of inhalation of bacteria, and their products, including endotoxins, derived from the environment and commensal organisms in the upper-respiratory tract. To deal with these commensal and pathogenic bacteria and their products, the lung has developed dynamic, multifaceted defense mechanisms. One important mechanism that characterizes initial (innate) immune defense in the lung is the rapid and vigorous recruitment of myeloid cells to sites of pathogen invasion or tissue damage. However, immune defense is clearly a double-edged sword, as the same features and functions that make it useful to the host can also damage lung tissues, ultimately impairing respiratory function and reducing alveolar gas exchange. Uncontrolled inflammation underlies several inflammatory diseases, including bacterial pneumonia, acute lung injury/acute respiratory distress syndrome, and the ischemia/reperfusion injury that occurs during lung transplantation. A better mechanistic understanding of respiratory immune responses, accompanied by a detailed delineation of the relevant molecular pathways, will constitute a critical step toward understanding disease pathogenesis and result in designing effective treatment and prevention strategies against these devastating inflammatory diseases. In this issue of the Journal of Leukocyte Biology, Sharma and colleagues [1] have shown a unique role for Clec4d (also known as Clecsf8), an orphan CLR, in the innate immune surveillance of lungs following pneumonia, caused by a Gram-negative pathogen, Kp. Their study addresses an essential and topical aspect of pneumonia biology. In general, Kp live in intestines and do not establish infections in individuals with strong immune systems. However, over the past decade, multidrug-resistant Kp strains have emerged as rapidly growing public health concerns in intensive care units, as these pathogens spread easily among extremely ill patients and kill more than one-half of those infected. In particular, carbapenem-resistant Kp infection may occur in numerous tissues/organs, including the lungs, where it produces serious sequelae, such as severe pneumonia and abscesses. The treatment of pneumonia can be difficult and expensive with prognostic outcomes often confounded by the age, overall health, and immune function of the patient; the emergence of multidrug-resistant pathogens worsens these problems. The mucosal innate immune defense against microbes involves membranebound, cytoplasmic, and soluble proteins, known as PRRs. These receptors recognize, bind, and activate immune signaling in response to specific PAMPs and/or endogenous ligands known as alarmins that emanate from dying or infected host cells. Together, PAMPs and alarmins are regarded as dangerassociated molecular patterns. The two widely studied PRRs include membranebound TLRs, which sense extracellular/ endosomal PAMPs, and cytoplasmic NLRs, which function as sensors of intracellular (endocytosed) PAMPs. The importance of TLRs and NLR inflammasomes in shaping a robust immune response during pneumonia and sepsis caused by Kp is well-established [2, 3]. Another category of PRRs includes CLRs, a protein superfamily of 1000 members found in multicellular organisms, from plants to invertebrates and vertebrates, including mammals [4]. A defining feature of the CLR superfamily is the presence of at least one CRD, which binds carbohydrate ligands in a Ca -dependent manner [4]. The CLRs may be soluble or transmembrane cellsurface molecules with an extracellular receptor domain and a cytoplasmic tail. From an immunological standpoint, CRD allows CLRs to function, not only as important innate-immune receptors that recognize carbohydrate PAMPs presented by prokaryotic (viruses, bacteria) and eukaryotic (fungi, protozoans, worms) pathogens but also in homeostasis to recognize and respond to alarmins. The presence of CLRs on the surface of myeloid cells and mucosal epithelium puts them at the forefront of innate-immune response modulation in the respiratory tract microenvironment.