Dermis resident macrophages orchestrate localized ILC2-eosinophil circuitries to maintain their M2-like properties and promote non-healing cutaneous leishmaniasis

Sang Hun Lee; Byunghyun Kang; Olena Kamenyeva; Tiago Rodrigues Ferreira; Kyoungin Cho; Jaspal S Khillan; Juraj Kabat; Brian L Kelsall; David L Sacks

doi:10.21203/rs.3.rs-2644705/v1

Dermis resident macrophages orchestrate localized ILC2-eosinophil circuitries to maintain their M2-like properties and promote non-healing cutaneous leishmaniasis

Res Sq [Preprint]. 2023 Apr 5:rs.3.rs-2644705. doi: 10.21203/rs.3.rs-2644705/v1.

Authors

Sang Hun Lee¹, Byunghyun Kang², Olena Kamenyeva³, Tiago Rodrigues Ferreira¹, Kyoungin Cho⁴, Jaspal S Khillan⁴, Juraj Kabat³, Brian L Kelsall², David L Sacks¹

Affiliations

¹ Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
² Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
³ Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Mouse Genetics and Gene Modification Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.

Abstract

Tissue-resident macrophages (TRMs) are critical for tissue homeostasis/repair. We previously showed that dermal TRMs produce CCL24 (eotaxin2) which mediates their interaction with IL-4 producing eosinophils, required to maintain their number and M2-like properties in the T_H1 environment of the Leishmania major infected skin. Here, we unveil another layer of TRM self-maintenance involving their production of TSLP, an alarmin typically characterized as epithelial cell-derived. Both TSLP signaling and IL-5⁺ innate lymphoid cell 2 (ILC2s) were shown to maintain the number of dermal TRMs and promote infection. Single cell RNA sequencing identified the dermal TRMs as the sole source of TSLP and CCL24. Development of Ccl24-cre mice permitted specific labeling of dermal TRMs, as well as interstitial TRMs from other organs. Genetic ablation of TSLP from dermal TRMs reduced the number of dermal TRMs, and disease was ameliorated. Thus, by orchestrating localized type 2 circuitries with ILC2s and eosinophils, dermal TRMs are self-maintained as a replicative niche for L. major.

Keywords: CCL24; IL-4; IL-5; ILC2; Leishmania major; TSLP; Tissue-resident macrophages; eosinophil.

Publication types

Preprint