We have identified a population of M2-like dermal macrophages that are present under steady state conditions and that are preferentially infected by a strain of Leishmania major isolated from a patient with chronic cutaneous lesions in a mannose receptor dependent fashion to promote non- healing cutaneous disease is conventionally resistant C57Bl/6 mice. The dermal macrophages are not replaced by blood precursors during infection, but are embryonic derived and locally maintained by IL-4 and IL-10 and retain M2 functionality despite the high levels of IFNg produced in the site. So far as we are aware, this is the first demonstration that the severity of cutaneous infection can be linked to the preferential targeting of M2-like dermis resident macrophages. The IL-4 dependence of the dermis resident macrophages has promoted us to try to identify the cellular source of this cytokine in the skin. Using IL-4 reported mice, intralesional T cells and eosinophils were shown to produce IL-4 during infection. By intravital imaging, eosinophils were found intimately associated with dermal macrophages, and eosinophil depletion reduced the number of dermal macrophages during infection, suggesting that they are the critical source of IL-4. We previously showed that infiltrating neutrophils efficiently phagocytose Leishmania major early after sand fly transmission or needle challenge, and the apoptotic clearance of infected neutrophils by dermal DCs results in immunosuppression of subsequent T cell responses. Besides DCs, tissue-resident macrophages are also specialized to engulf apoptotic cells and this process is known to be critical to maintain their anti-inflammatory properties. Recent data from our group showed that M2-like dermal macrophages promote a chronic cutaneous infection by providing a replicative niche to a non-healing strain of L. major in C57Bl/6 mice. We hypothesized that dermal macrophages can phagocytose apoptotic infected neutrophils which would contribute to their ability to maintain their M2-like properties during strong Th1 immunity. Our data show that L. major induces apoptosis in neutrophils and these apoptotic neutrophils are efficiently captured and cleared by dermal macrophages. When we treated infected, apoptotic neutrophils with annexin V to block their phosphatidylserine-mediated phagocytosis, clearance of neutrophils by dermal macrophages in vivo was decreased. This was accompanied by phenotypic changes in the dermal macrophages, including down-regulation of receptors for apoptotic cells, such as Axl and Tim-4. By intravtial imaging, dermal macrophages could be observed engulfing neutrophils that were recruited to the site of infection by sand fly bite. Thus, our data suggest that dermal macrophages are the major phagocytes to clear apoptotic neutrophils which helps to maintain their anti-inflammatory functions and their role in L. major persistence.
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