In this?Perspective article?we discuss the evidence for synergistic anti-inflammatory and immunomodulatory properties exerted by vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors, the latter being a class of antihyperglycemic agents used for the treatment of Type 2 diabetes, which have also been reported as immunomodulators. achievement of adequate serum 25-hydroxyvitamin D (25[OH]D) levels, which amount to approximately 40C60?ng/ml . The aforementioned properties are exerted by the biologically active form of vitamin D, which is also referred to as 1, 25-dihydroxyvitamin D3 or calcitriol. It has been shown that vitamin D plays a central role in the regulation of innate and adaptive immune responses, promoting antiviral effector mechanisms, reducing the expression of pro-inflammatory cytokines and inducing tolerogenic responses [16C18]. In particular, calcitriol has been shown to: upregulate the transcription of antimicrobial peptides (such as cathelicidin and defensin 2) in various human cell lines (myeloid cells, monocytes/macrophages, neutrophils and keratinocytes);?promote the differentiation of monocytes/macrophages and enhance their chemotactic and phagocytic capacity;?inhibit the production of several pro-inflammatory cytokines (e.g., IL-6 and TNF-) by monocytes and macrophages;?decrease macrophage antigen-presentation and T-cell stimulatory ability;?elicit the shift of macrophage polarization from the M1 pro-inflammatory phenotype (classically activated macrophages)?towards the M2 anti-inflammatory phenotype (alternatively activated macrophages);?render the dendritic cells more tolerogenic and reduce their antigen-presenting capacity;?upregulate regulatory T cells; and?favor the shift of T cells from an effector pro-inflammatory phenotype toward a regulatory anti-inflammatory phenotype by reducing Th1 and Th17 cell differentiation and promoting Th2 cell differentiation [16,17]. Importantly, vitamin D receptor?has been identified in almost all immune cells , as well as in human airway epithelial cells . The nearly ubiquitous expression Aldicarb sulfone of vitamin D receptor enables vitamin D to exert its Mouse monoclonal to CD3/HLA-DR (FITC/PE) pleiotropic actions, including the regulation of local respiratory homeostasis by upregulating the expression of antimicrobial peptides and/or by directly affecting the replication of respiratory viruses . Vitamin D deficiency (defined as serum 25-hydroxyvitamin D levels less than 20?ng/ml) is a global health issue afflicting more than one billion children and adults worldwide . Since the beginning of COVID-19 pandemic, vitamin D deficiency has been suggested as an independent risk factor for SARS-CoV-2 infection and hospitalization, development of cytokine storm and poor outcomes related to COVID-19 [21C26]. Moreover, the overlap between risk factors for vitamin D deficiency and severe manifestations of COVID-19 (such as Black or Aldicarb sulfone Asian ethnic origin, living at higher latitudes, older age and obesity) [27,28] led researchers to consider vitamin D deficiency and COVID-19 as two related pandemics . In a large US retrospective, observational study involving more than 190,000 patients with SARS-CoV-2 results from all 50 states, vitamin D deficiency has been associated with significantly higher SARS-CoV-2 positivity rates . Interestingly, the decrease in SARS-CoV-2 positivity rate associated with 25(OH)D levels appeared to plateau as values approached 55?ng/ml, suggesting that additional benefits exist when 25(OH)D levels are higher than the cut-off value used Aldicarb sulfone to define vitamin D sufficiency for bone health?(30?ng/ml) . Several observational studies have showed that hospitalized patients with COVID-19 exhibit a markedly high prevalence of hypovitaminosis D, and that?vitamin D deficiency is associated with a more advanced disease radiologic stage, along with a significantly higher risk of noninvasive mechanical ventilation and in-hospital mortality [31C35]. It has also been shown that serum vitamin D levels are significantly lower in severe/critical COVID-19 cases compared with mild-to-moderate cases . We recently showed that a lower vitamin D status upon admission is significantly and independently associated with an increased risk of COVID-19-related in-hospital mortality . A systematic review and meta-analysis of observational Aldicarb sulfone studies conducted by Pereira  confirmed a positive association between vitamin D deficiency and COVID-19 severity. In this regard, it is Aldicarb sulfone worth mentioning that acute illness and systemic inflammatory response can further lower circulating 25(OH)D levels [38,39], thus explaining, at least in part, the high frequency of severe vitamin D deficiency observed in patients with infectious diseases, including COVID-19 complicated by cytokine release syndrome. Given the abovementioned anti-inflammatory and immunomodulatory properties of vitamin D, vitamin D deficiency may exacerbate COVID-19 severity and mortality by triggering the hyperinflammatory state and the cytokine storm associated with the most severe cases. Indeed, patients with COVID-19 and vitamin D deficiency have been shown to exhibit significantly higher serum.