Platelet-macrophage cooperation drives IL-33-dependent type 2 lung immunopathology in a sex-biased manner.

Abstract

Platelets amplify lung type 2 inflammation (T2I), but the underlying mechanisms remain incompletely understood. We elucidated the platelet-driven T2I mechanisms, particularly the role of platelet-derived leukotriene C₄ (LTC₄). We assessed lung T2I to Alternaria alternata extract in vivo using mice with targeted deletions of Ltc4s in platelets, macrophages (Macs), or mast cells (MCs); Il33 in Macs, hematopoietic cells, or alveolar type 2 (AT2) cells; and cysteinyl leukotriene receptors. Exogenous administration of LTC₄ and IL-33 in naïve mice complemented the genetic models. Sex- and age-matched mice were randomly assigned, and histopathologic evaluations were performed under blinded conditions. Platelets promoted IL-33 expression in perivascular Macs and induced transcellular LTC₄ synthesis. Although platelet Ltc4s was not needed to induce IL-33⁺ Macs, it promoted both IL-33⁺ AT2 cell and group 2 innate lymphoid cell expansions in a sex-biased manner. Platelet depletion abrogated A alternata-induced increases in IL-33 and AT2 cell expansion. Platelet-adherent Macs expressed higher IL-33 than no-adherent counterparts. Platelet-specific Ltc4s deletion reduced eosinophil, group 2 innate lymphoid cell, and AT2 cell expansion in female animals in a delayed manner. Mac-specific Il33 deletion eliminated platelet-driven IL-33 increases and attenuated AT2 cell expansion selectively in female animals. Exogenous LTC₄ and IL-33 synergistically induced IL-33⁺ Macs and expanded AT2 cells. Adherent platelets rapidly upregulate IL-33-expressing Macs, and platelet-derived LTC₄ sustains IL-33-driven expansion of AT2 cells and group 2 innate lymphoid cells, driving sex-biased amplification of T2I. This platelet-Mac axis may contribute to sex differences in type 2 inflammatory airway diseases such as asthma.