Neutrophils differentially attenuate immune response toAspergillusinfection through complement receptor 3 and induction of myeloperoxidase

Abstract

Invasive aspergillosis (IA) remains a major cause of morbidity in immunocompromised hosts. This is due to the inability of the host immunity to respond appropriately to Aspergillus. An established risk factor for IA is neutropenia that is encountered by patients undergoing chemotherapy. Herein, we investigate the role of neutrophils in modulating host response to Aspergillus. We found that neutrophils had the propensity to suppress proinflammatory cytokine production but through different mechanisms for specific cytokines. Cellular contact was requisite for the modulation of interleukin-1 beta production by Aspergillus with the involvement of complement receptor 3. On the other hand, inhibition of tumour necrosis factor-alpha production (TNF-α) was cell contact-independent and mediated by secreted myeloperoxidase. Specifically, the inhibition of TNF-α by myeloperoxidase was through the TLR4 pathway and involved interference with the mRNA transcription of TNF receptor-associated factor 6/interferon regulatory factor 5. Our study illustrates the extended immune modulatory role of neutrophils beyond its primary phagocytic function. The absence of neutrophils and loss of its inhibitory effect on cytokine production explains the hypercytokinemia seen in neutropenic patients when infected with Aspergillus.

The regulatory roles of neutrophils in adaptive immunity

“…For example, the modulation of IL-1β production by Aspergillus is cellular contact-dependent with the involvement of complement receptor 3. Inhibition of TNF-α is cell contact-independent and mediated by secreted MPO through the TLR4 pathway [86]. Furthermore, there are two waves of neutrophils entering dLNs after immunization.…”

Exploring the Effect of Hepatitis B e Antigen on Neutrophil Activation and Natural Killer Cell Dysfunction in Patients with Chronic Hepatitis B

“…Neutrophils are abundant in peripheral circulation, are well characterized in host defense against bacteria, and play a signi cant role in shaping adaptive immunity [30]. A recent study showed that neutrophils inhibited IL-1β and TNF-α production by CD14 + monocytes in cell-cell contact-dependent and independent manners [31]. Moreover, neutrophils have the capacity to inhibit T-cell proliferation through the expression of Mac-1 and ROS during acute in ammation [32].…”

An adult autosomal recessive chronic granulomatous disease patient with pulmonary Aspergillus terreus infection

“…A. Terreus infection often leads to superficial infections in man whereby the inhalation of spores initiates the immediate recruitment and activation of macrophages and neutrophils that overwhelms the infection [ 38 ]. However, in immunosuppressed individuals with neutropenia, or with a compromised capacity for neutrophil phagocytosis, this response is less vigorous [ 39 ].…”