Critical role for complement receptor 3 (CD11b/CD18), but not for Fc receptors, in killing of Streptococcus pyogenes by neutrophils in human immune serum

Abstract

During phagocytosis, surface receptors on neutrophils interact with pathogens opsonized with complement factor C3b/iC3b and in some cases with antibodies. In human immune sera antibodies directed against surface‐bound M proteins mediated killing of Streptococcus pyogenes by neutrophils. Surprisingly, blocking of the Fc receptors had little effect on the killing. In contrast, inhibition of C3b/iC3b generation, or blocking of the major neutrophil iC3b receptor CD11b/CD18, enabled S. pyogenes to grow efficiently in immune sera. Inhibition of CD11b/CD18, but not of CD32, the major neutrophil signaling Fc receptor, prevented Streptococcus‐induced NADPH oxidase‐dependent respiratory burst, and blocking of C3b/iC3b formation inhibited Streptococcus‐induced activation of Cdc42, a small GTPase critically involved in transmitting pro‐inflammatory signals to the cytoskeleton. Consequently, ligation of CD11b/CD18 by bacteria‐bound iC3b is necessary for inducing a neutrophil response leading to elimination of S. pyogenes in immune human serum.

Group A Streptococcal Cysteine Protease Degrades C3 (C3b) and Contributes to Evasion of Innate Immunity

“…Interestingly, inhibition of the Fc region of anti-M antibodies revealed low inhibition to eliminate S. pyogenes by neutrophils. In contrast, blocking of iC3b or the major iC3b receptor CD11b/CD18 led to growth of S. pyogenes (35). Also both iC3b and its receptor demonstrated critical roles in killing S. pyogenes by neutrophils in the innate immune system.…”

“…Finally, in the current study, we showed that SpeB can directly degrade and inhibit the function of C3 (C3b). C3 (C3b) degradation is very important to decrease innate immunity (35). Interestingly, inhibition of the Fc region of anti-M antibodies revealed low inhibition to eliminate S. pyogenes by neutrophils.…”

Airway Inflammation and Upregulation of β2 Mac‐1 Integrin Expression on Circulating Leukocytes of Female Ragpickers in India

“…Since microorganisms are abundant in organic matter of urban wastes 16) , ragpickers seem more prone to infection that requires activation of the immune system. Neutrophils could play a crucial role in this context as they are highly efficient in defense against invading pathogens through β 2 Mac-1 integrin, the major receptor for complement iC3b 17) . Interaction of C3b/iC3b with integrin mediates pathogen uptake, activation of the NADPH system, induction of respiratory burst, and release of reactive oxygen species that destroy the pathogen 17) .…”

“…Neutrophils could play a crucial role in this context as they are highly efficient in defense against invading pathogens through β 2 Mac-1 integrin, the major receptor for complement iC3b 17) . Interaction of C3b/iC3b with integrin mediates pathogen uptake, activation of the NADPH system, induction of respiratory burst, and release of reactive oxygen species that destroy the pathogen 17) . The importance of this integrin in host defense can be judged from the report that showed facilitation of bacterial growth following blockade of leukocyte CD11b/CD18 17) .…”

“…Interaction of C3b/iC3b with integrin mediates pathogen uptake, activation of the NADPH system, induction of respiratory burst, and release of reactive oxygen species that destroy the pathogen 17) . The importance of this integrin in host defense can be judged from the report that showed facilitation of bacterial growth following blockade of leukocyte CD11b/CD18 17) . Neutrophils are among the first cells to respond to inflammation, and circulating platelets help them in this endeavor, first by self-activation, then by mediating integrin expression on the neutrophil surface through release of P-selectin from alpha granules and adenosine tri-and diphosphate from dense bodies 18) .…”