Impaired Host Defense, Hematopoiesis, Granulomatous Inflammation and Type 1–Type 2 Cytokine Balance in Mice Lacking CC Chemokine Receptor 1

TLDR

CCR1 is a chemokine receptor expressed on neutrophils, monocytes, lymphocytes, and eosinophils that binds MIP‑1α and related chemokines, while other CCR subtypes share overlapping but distinct specificities, indicating both redundant and unique roles. The study generated CCR1‑knockout mice to investigate CCR1’s roles in hematopoiesis, host defense, and granuloma formation. CCR1‑knockout mice were created via targeted gene disruption. CCR1 deficiency disrupted myeloid progenitor trafficking and proliferation, impaired neutrophil chemotaxis and mobilization, accelerated mortality to Aspergillus fumigatus, reduced lung granuloma size, and shifted cytokine production toward a type‑1 response, underscoring CCR1’s essential functions in hematopoiesis, host defense, and inflammation.

Abstract

CC chemokine receptor 1 (CCR1) is expressed in neutrophils, monocytes, lymphocytes, and eosinophils, and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1α, as well as several related CC chemokines. Four other CCR subtypes are known; their leukocyte and chemokine specificities overlap with, but are not identical to, CCR1, suggesting that CCR1 has both redundant and specific biologic roles. To test this, we have developed CCR1-deficient mice (−/−) by targeted gene disruption. Although the distribution of mature leukocytes was normal, steady state and induced trafficking and proliferation of myeloid progenitor cells were disordered in −/− mice. Moreover, mature neutrophils from −/− mice failed to chemotax in vitro and failed to mobilize into peripheral blood in vivo in response to MIP-1α. Consistent with this, −/− mice had accelerated mortality when challenged with Aspergillus fumigatus, a fungus controlled principally by neutrophils. To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in −/− mice compared to +/+ littermates. This was associated with increased interferon-γ and decreased interleukin-4 production in −/− versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1–type 2 cytokine balance. Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.