CX3CR1-expressing myeloid cells regulate host-helminth interaction and lung inflammation

Many helminth life cycles, including hookworm, involve a mandatory lung phase, wheremyeloid and granulocyte subsets interact with the helminth and respond to infection-inducedlung injury. To evaluate these innate subsets, we employed Nippostrongylus brasiliensisinfection of reporter mice for myeloid cells (CX3CR1 GFP ) and granulocytes (PGRP dsRED ).Nippostrongylus infection induced lung infiltration of reporter cells, including CX3CR1 +myeloid cells and PGRP + eosinophils. Strikingly, CX3CR1 GFP/GFP mice, which are deficient inCX3CR1, were protected from Nippostrongylus infection with reduced weight loss, lunginflammation, and worm burden compared to CX3CR1 +/+ mice. This protective effect wasspecific for CX3CR1 as CCR2-deficient mice did not exhibit reduced worm burdens.Nippostrongylus co-culture with lung Ly6C + monocytes or CD11c + cells revealed thatCX3CR1 GFP/GFP monocytes secreted more inflammatory cytokines, and actively bound theparasites causing reduced motility. RNA sequencing of Ly6c + or CD11c + cells revealed thatNippostrongylus induced gene expression changes, particularly in monocytes, associated withcytokine/chemokine signaling and cell adhesion and matrix remodeling pathways. We alsoidentified cytotoxic and adhesion molecules as potential effectors against the parasite, such asgranzyme and tgm2, which were elevated in CX3CR1 GFP/GFP monocytes. These studies validatea dual innate cell reporter for lung helminth infection and demonstrate that CX3CR1 impairsmonocyte-helminth interaction.