Contrasting Effects of CCR5 and CCR2 Deficiency in the Pulmonary Inflammatory Response to Influenza A Virus

Abstract

The immune response to influenza A virus is characterized by an influx of both macrophages and T lymphocytes into the lungs of the infected host, accompanied by induced expression of a number of CC chemokines. CC chemokine receptors CCR5 and CCR2 are both expressed on activated macrophages and T cells. We examined how the absence of these chemokine receptors would affect pulmonary chemokine expression and induced leukocyte recruitment by infecting CCR5-deficient mice and CCR2-deficient mice with a mouse-adapted strain of influenza A virus. CCR5 ؊/؊ mice displayed increased mortality rates associated with acute, severe pneumonitis, whereas CCR2 ؊/؊ mice were protected from the early pathological manifestations of influenza because of defective macrophage recruitment. This delay in macrophage accumulation in CCR2 ؊/؊ mice caused a subsequent delay in T cell migration, which correlated with high pulmonary viral titers at early time points. Infected CCR5 ؊/؊ mice and CCR2 ؊/؊ mice both exhibited increased expression of the gene for MCP-1, the major ligand for CCR2؊/؊ and a key regulator of induced macrophage migration. These studies illustrate the very different roles that CCR5 and CCR2 play in the macrophage response to influenza infection and demonstrate how defects in macrophage recruitment affect the normal development of the cell-mediated immune response.

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2–/– mice

“…Nevertheless, contrary to the results of Dawson et al [3], CCR2 deficiency did not augment neutrophil persistence in the infected lungs (Fig. Fig.…”

“…However, CCR2Ϫ/Ϫ mice experienced a significant delay in the recruitment of monocyte/ macrophages in the BAL at Days 5 and 7 after infection compared with ϩ/ϩ controls. Increased neutrophil infiltration of the airways of CCR2Ϫ/Ϫ mice had been observed previously at Day 5 after influenza infection [3]. In the present study, we found neutrophil infiltration of the airways occurred between Days 3 and 30 after infection in CCR2ϩ/ϩ and Ϫ/Ϫ mice.…”

“…In the present study, we showed that as well as MCP-1 and IP-10, several other chemokines were induced during airway inflammation. However, differences in the kinetics of chemokine expression were apparent, and Dawson et al [3] reported peak induction of MCP-1 and IP-10 3-5 days earlier than observed in the present studies. The differences observed could be attributable to different infectious dose regimens used in the two studies.…”

Role of C‐C chemokine receptors 1 and 5 and CCL3/macrophage inflammatory protein‐1α in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production

“…CCR5 binds to multiple chemokines including CCL3, CCL4/ MIP-1b, and CCL5 [19,20]. CCR5-deficient (CCR5 -/-) mice exhibited reduced numbers of infiltrating leukocytes upon infection with parasites and viruses, compared with wild-type mice, with changes in susceptibility to these pathogens [21][22][23][24][25][26].…”

Variants of CCR5, which are permissive for HIV-1 infection, show distinct functional responses to CCL3, CCL4 and CCL5

“…30 Furthermore, CCR5-deficient mice, which exhibit diminished TH1 polarization, 31 are more susceptible to viral and bacterial challenge. 32,33 These studies indicate that activation of CCR5 favors cell-mediated immune responses that promote both host defense against infection and chronic inflammatory diseases.…”