Resilience of dermis resident macrophages to inflammatory challenges

Abstract

The skin serves as a complex barrier organ populated by tissue-resident macrophages (TRMs), which play critical roles in defense, homeostasis, and tissue repair. This review examines the functions of dermis resident TRMs in different inflammatory settings, their embryonic origins, and their long-term self-renewal capabilities. We highlight the M2-like phenotype of dermal TRMs and their specialized functions in perivascular and perineuronal niches. Their interactions with type 2 immune cells, autocrine cytokines such as IL-10, and their phagocytic clearance of apoptotic cells have been explored as mechanisms for M2-like dermal TRM self-maintenance and function. In conclusion, we address the need to bridge murine models with human studies, with the possibility of targeting TRMs to promote skin immunity or restrain cutaneous pathology.

Fig. 1. The mechanisms by which dermal TRMs maintain an M2-like phenotype and serve as a replicative niche for L. major.

The left side of the figure illustrates the initial establishment of L. major infection within the dermis. The transmitted metacyclic form of L. major, introduced by either an infected sand fly or experimental needle injection, is quickly phagocytosed by TRMs or by neutrophils that swarm to the transmission site. Inside the phagolysosome, the parasite transforms into the amastigote form, which is the intracellular stage of Leishmania in the mammalian host. Inflammatory monocytes are subsequently recruited to the site and become the dominant cells harboring parasites during the development of the cutaneous lesion. Following a robust T_H1 immune response induced in the local draining lymph nodes, antigen-specific CD4⁺ and CD8⁺ T cells are recruited back to the site and release mediators, including IFNγ, TNFα, granzyme B (GzmB), and perforin (PFN), which activate infected monocytes and monocyte-derived cells to kill the parasite via their production of reactive oxygen species (ROS) and nitric oxide (NO). In contrast, TRMs employ various mechanisms to maintain their M2-like properties and promote parasite persistence, including their capacity to (1) orchestrate localized interactions with type 2 immune cells, including group 2 innate lymphoid cells (ILC2s) and eosinophils; (2) produce anti-inflammatory cytokines (e.g., IL-10) that operate in an autocrine fashion; and (3) engage in apoptotic cell clearance via receptors, including the TYRO3/AXL/MERTK family of receptor tyrosine kinases, which imprint an anti-inflammatory program on TRMs.