CCR1 and CC Chemokine Ligand 5 Interactions Exacerbate Innate Immune Responses during Sepsis

Abstract

CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1−/−) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1−/− mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leukocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1−/− resident or recruited peritoneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1−/− mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-γ and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention.

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease

“…Such SNPs could reside in candidate chemokine receptor genes involved in immunity and located nearby, such as CCR9, XCR1 or, more particularly, CCR1, which is directly adjacent to the CCR3 gene [38]. CCR1 plays important roles in leucocyte trafficking, pathogen clearance and type 1/type 2 cytokine balance, acting -similarly to CCR5 -as a major receptor for the chemokines MIP-1a and RANTES [39][40][41]. However, functional SNPs have not yet been described in the CCR1 gene.…”

RANTES gene polymorphisms (-403G>A and -28C>G) associated with hepatitis B virus infection in a Saudi population

“…RANTES promotes T-cell activation and proliferation. The binding of RANTES to its alternate receptor, CCR1, has been shown to upregulate the inflammatory response during sepsis (Ness et al, 2004) and to increase recruitment of natural killer cells to the liver in an autoimmune hepatitis mouse model (Ajuebor et al, 2007). Consistent with the pivotal role of RANTES in the adaptive immunity, the RANTES gene is considered to be the candidate gene in modulating the host response to HBV infection.…”

“…The data in our study suggest that RANTES -403A and -28G would enhance recovery from an HBV infection. These findings could be explained by the characteristics of the cellular and cytokine profiles found in the conconavalin A (Con A)-induced hepatitis mouse model (Ness et al, 2004). In this model, natural killer (NK) cells did not infiltrate the liver in the wild-type mouse after Con A treatment, but accumulated in the liver of CCR5 deficient mice upon Con A treatment, a condition that would apparently enhance an immune response and aid in the spontaneous recovery from HBV infection.…”

Substance P in Polymicrobial Sepsis: Molecular Fingerprint of Lung Injury in Preprotachykinin-A−/− Mice

“…The precise mechanism of protection is not clear yet. Interestingly, CCL-3, CCL-6 and CXCL-10 have been demonstrated to be protective in sepsis-induced injury and mortality in a murine CLP model (21,(23)(24)(25). Macrophage-derived chemokine (MDC) (CCL-22) also protected mice against CLP-induced death (26).…”

“…Pathway analysis further provides an insight into the complex network of interactions among these proinflammatory chemokines. The role of chemokine receptors in sepsis is not very clear (21). Cytokines are considered both friend and foe in sepsis (5).…”