CCR7-guided neutrophil redirection to skin-draining lymph nodes regulates cutaneous inflammation and infection

Abstract

Neutrophils are the first nonresident effector immune cells that migrate to a site of infection or inflammation; however, improper control of neutrophil responses can cause considerable tissue damage. Here, we found that neutrophil responses in inflamed or infected skin were regulated by CCR7-dependent migration and phagocytosis of neutrophils in draining lymph nodes (dLNs). In mouse models of Toll-like receptor–induced skin inflammation and cutaneous Staphylococcus aureus infection, neutrophils migrated from the skin to the dLNs via lymphatic vessels in a CCR7-mediated manner. In the dLNs, these neutrophils were phagocytosed by lymph node–resident type 1 and type 2 conventional dendritic cells. CCR7 up-regulation on neutrophils was a conserved mechanism across different tissues and was induced by a broad range of microbial stimuli. In the context of cutaneous immune responses, disruption of CCR7 interactions by selective CCR7 deficiency of neutrophils resulted in increased antistaphylococcal immunity and aggravated skin inflammation. Thus, neutrophil homing to and clearance in skin-dLNs affects cutaneous immunity versus pathology.

Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection

“…1I). We also studied an established cutaneous ear infection model with S. aureus ( 32 ), where, again, BALB/c mice showed a significantly higher bacterial load compared with B6 mice (Fig. 1J).…”

“…We surmised that IL-4–exposed neutrophils exhibiting an aged phenotype would be more likely to be cleared by phagocytic cells, which is a previously described anti-inflammatory mechanism ( 36 ). We tested this hypothesis in mice by intracellular Ly6G staining (termed Ly6G intra ) ( 32 ) of the two major cell subsets phagocytosing neutrophils, macrophages (CD11c inter F4/80 high ) and dendritic cells (DCs; CD11c high MHC II high ). In contrast to surface Ly6G (Ly6G surf ) expression on neutrophils, Ly6G surf was absent on macrophages and DCs; however, macrophages and DCs contained varying amounts of Ly6G intra (Fig.…”

“…Others have suggested that neutrophil aging, at least on a transcriptional level, could also be interpreted as increasing activation by extrinsic signals (27). Such cues can occur during infection and inflammation and result in the up-regulation of certain chemokine receptors on neutrophils, which, in turn, destine neutrophils for clearance (32). Another concept, stemming from studies of neutrophils in cancer, distinguishes N1 and N2 neutrophils showing antitumorigenic and protumorigenic behavior, respectively and DCs (CD11c + MHC II + ) in the spleen of naïve B6 Il4ra +/+ mice, BALB/c Il4ra +/+ mice, and BALB/c Il4ra −/− mice shown as percentages of total neutrophils (left) and counts of phagocytosing cells (right).…”

“…Both LM and S. aureus were cultured in brain heart infusion media (Oxoid) and injected intravenously into mice in sterile PBS (Gibco). For the cutaneous ear infection model with S. aureus , the ear piercing method was used, as previously described ( 32 , 57 ). Briefly, ears of mice were pierced 10 times with a 30-gauge insulin needle to allow entry of bacteria, followed by application of a 20-μl droplet of S. aureus (10 14 CFU/ml).…”

Identification of Effective Diagnostic Biomarkers and Immune Cell Infiltration in Atopic Dermatitis by Comprehensive Bioinformatics Analysis

“…After CCR7 −/− mouse bone marrow-derived DCs were subcutaneously injected into wild-type mice, these cells were unable to travel to the lymph nodes and access lymphatic drainage, which indicates that DCs also need to express CCR7 to facilitate their homing to lymph nodes ( Hintzen et al, 2006 ). Moreover, it has been reported that the movement of neutrophils from skin to skin-draining lymph nodes via lymphatic vessels was also mediated by CCR7 ( Özcan et al, 2022 ). In the present study, we found that the CCR7 expression level was upregulated in AD patients.…”