S904 THE FUNCTIONAL RESPONSE OF IRON‐RECYCLING AND INFECTION CONTROL‐SPECIALIZED MACROPHAGES IS IMPAIRED BY TRANSFUSIONS AND AMELIORATED BY IRON CHELATION
Authors: Passos S. , Sparla R. , Rauner M. , Weidner H. , Yazdanbakhsh K. , Platzbecker U. , Muckenthaler M.U. , Vinchi F. 
Published: June 2019

Background:

Iron overload is common in anemic patients who require regular transfusions. Transfusional iron overload is associated with enhanced susceptibility to infections, a common cause of morbidity/mortality in these patient populations.

Aims:

Here we studied how iron overload, besides supporting bacterial growth, may alter macrophage response to infectious stimuli.

Methods:

We applied a mouse model of repeated allogeneic RBC transfusions and investigated the impact of transfusions on the phenotypic plasticity of different macrophage populations as well as their responses to infectious cues.

Results:

Using this model, we have recently shown that repeated transfusions promote macrophage switching to a M2‐like anti‐inflammatory phenotype, hallmarked by reduced inflammatory marker expression and inflammatory cytokine release. Consistently, in transfused animals, macrophages develop a blunted M1‐like inflammatory phenotype in response to LPS, leading to reduced circulating inflammatory cytokines. These observations indicate that transfusion‐induced erythrophagocytosis dampens the inflammatory response to infectious cues by impairing macrophage functions. Transfusion‐blunted M1 polarization occurs in both iron‐recycling hepatic Kupffer cells and splenic red pulp macrophages (RPM). We now have extended our analysis to additional macrophage sub‐populations of the spleen which play a critical role in the phagocytosis of blood‐borne pathogens and control of innate/adaptive immune response to infections and found that also these cells, marginal zone (MZM) and marginal metallophilic (MMM) macrophages, are affected by RBC transfusions and show a suppression of M1 markers. Since MZMs and MMMs are not directly involved in erythrophagocytosis, we speculate that the blunted M1 polarization of iron‐recycling macrophages attenuates the pro‐inflammatory activation of other macrophages, including MZMs and MMMs, with potential impact on the susceptibility and response to infections. We now have administered an iron chelator, deferasirox, during the transfusion period, and show that iron chelation therapy partially restores the phenotype of Kupffer cells and RPMs by rescuing marker expression and shifting the transfusion‐triggered M2‐like macrophage population to a M1‐like (both with and without LPS). Interestingly, chelation therapy significantly improves the expression of M1 markers also in MZMs and MMMs, suggesting that chelation would help to control infections by improving the response of different macrophage sub‐populations. Importantly, we have confirmed our findings in a mouse model of MDS receiving repeated transfusions. Combined with marked cytopenias and iron‐boosted microorganism growth, the weak pro‐inflammatory activation of macrophages might contribute to the increased propensity of transfused MDS patients to develop infections.

Summary/Conclusion:

Our data indicate that transfusions blunt macrophage inflammatory response by affecting macrophage plasticity towards an anti‐inflammatory phenotype with reduced potential to counteract infections. By restoring cell polarization, iron chelation likely improves the functional response of macrophages to invading microorganisms. Transfusion practice might therefore increase the risk of infections not solely through increased iron availability to microorganisms, but also through the impaired activation of a broad plethora of macrophages, involved in iron recycling and infection control. Transfused patients might benefit from chelation by both restricting iron from pathogens and improving macrophage‐induced immune response.