Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia

Abstract

Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.

ZIP8-Mediated Intestinal Dysbiosis Impairs Pulmonary Host Defense against Bacterial Pneumonia

“…Collectively, these highly conserved transporters regulate Zn homeostasis under normal and stress-induced conditions in mammals. Our group discovered that ZIP8 is indispensable in myeloid cell-mediated host defense against pneumococcus in the lung through the alteration of Zndependent cell signaling networks that influence the immune response [37]. Furthermore, it has been shown in humans and in animal models that aging is a predisposing factor for Zn deficiency, which can adversely impact both innate and adaptive immunity [16,17,[38][39][40].…”

“…All methods involving animal care and procedures in this research protocol were performed in accordance with the NIH and Office of Laboratory Animal Welfare (OLAW) guidelines. Conditional Zip8 knockout mice, referred to as Zip8KO, were generated, as previously described [22,37]. Briefly, heterozygous Zip8flox-neo/+ mice were bred with ROSA26:FLPe knock-in mice (The Jackson Laboratory, Bay Harbor, ME, USA) with a ubiquitous expression of FLP1 recombinase to delete the Neo cassette adjacent to the upstream loxP site.…”

“…Zip8flox/flox mice were crossed with myeloid cell-specific LysMcre (The Jackson Laboratory) to generate the conditional Zip8KO. LysMcre-mediated Zip8 deletion was confirmed in lung myeloid cells at baseline and 24 h post-LPS stimulation using a ROSA reporter (as previously described) [37]. C57BL/6J wild-type counterparts were purchased from Jackson Labs and bred for experimental procedures.…”

Nutritional immunity: the battle for nutrient metals at the host–pathogen interface

“…Further, Zn deficiency results in increased expression of virulence factors of enteric pathogens including enteropathogenic E. coli 207 , 208 . Animals deficient in Zn uptake exhibit increased susceptibility to bacterial infection 209 , as is seen in Zip8 -knockout mice infected with Streptococcus pneumonia 210 . Reduced levels of Cu are associated with neutropenia and, therefore, increase infectious disease risks by pathogens such as S. enterica and Mannheimia haemolytica in animal models 211 , 212 .…”

Equilibrative Nucleoside Transporter 3 is an IFN-stimulated Gene that Facilitates Viral Genome Release

“…The expression of metabolite transporters is also a prerequisite for the differentiated myeloid cells or B cells to perform their functions. Glut1 is indispensable for the inflammatory response of macrophages(Freemerman et al , 2014); Zinc transporter participates in the phagocytosis and cytokine production of dendritic cells (DCs) and macrophages(Hall et al , 2021) as well as the B cell development(Anzilotti et al , 2019). These observations demonstrate the importance of metabolite transporter and immune effectors and raise the interesting question of how the sensing of threat is translated into metabolic reprogramming.…”