Vitamin D Prevents the Maladaptive Cycle of Local Inflammation
and Secondary Injury that Leads to Poorer
Outcomes
A recent large-scale epidemiological study suggested a possible link
between vitamin D deficiency and the severity of COVID-19 cases among
patients in the USA, France and the United Kingdom(84). This study
correlated the low serum level of vitamin D with a higher C-reactive
protein (CRP) level in COVID-19 patients based on previous findings(85,
86). In fact, multiple observational and intervention studies have
suggested the beneficial effects of vitamin D on reducing circulating
CRP and pro-inflammatory cytokines(86-90). This has a beneficial impact
in lowering a heightened inflammation state that is associated with
poorer outcomes(91-93). Vitamin D also modulates the renin-angiotensin
cascade(94). A high expression of angiotensin converting enzyme (ACE)
and angiotensin II, coupled with reduced expression of angiotensin
converting enzyme 2 (ACE2) are common features in a pro-inflammatory
state in acute respiratory distress syndrome (ARDS). Vitamin D reduces
the susceptibility to acute lung injury (ALI) by inhibiting renin
thereby angiotensin II biosynthesis(95-98). This may have a protective
effect in preventing a “cytokine storm” that is often implicated in
severe COVID-19 cases(84, 99).
Vitamin D also enhances the production of interleukin-10 (IL-10), a
cytokine with potent anti-inflammatory properties(100). Increasing IL-10
favours the proliferation and differentiation of T helper cell 2 (Th2)
and T regulator (T reg) cells over T helper cell 1 (Th1) and T helper
cell 17 (Th 17) (101, 102). This could have an effect in promoting
tolerance and controlling an exacerbated immune response(41).
Furthermore, vitamin D supplementation reduces the expression of
pro-inflammatory cytokines and increases the expression of
anti-inflammatory cytokines by macrophages, by enhancing expression of
MAPK phosphatase-1 and suppressing p38 activation(103-105). A persistent
immune activation leads to an increased mortality in HIV patient.
Vitamin D protects against the development of immune reconstitution
inflammatory syndrome events in HIV patients, likely through
downregulating CD38 expression on the surface of memory
CD8+ T cells(106, 107). Vitamin D also decreases the
expression of major histocompatibility complex (MHC) class II and their
co-stimulatory molecules such as CD80, thereby decreasing T cell
activation with persistent antigen presentation(108). It could be
posited that these anti-inflammatory properties of vitamin D could have
beneficial impacts on patients suffering from severe form of COVID-19.
In animal studies, it has been shown that vitamin D can reduce the
severity of coronavirus illness such as the enteropathogenic porcine
epidemic diarrhoea virus (PEDV)(109). Adding 155.5µg/kg diet 25(OH)D to
the feed given to weaned pigs can have a protective effect on
PEDV-induced inflammation and alleviate damage to the intestinal
tracts(109). This is achieved by regulating autophagy, enhancing
cathelicidins production and inhibiting jejuna mucosa interleukin-6
(IL-6) and interleukin-8 (IL-8) mRNA expression, hence lessening the
severity of damage(109-111). The VDR-knockout mice model has
demonstrated that vitamin D has protective effects on the integrity of
epithelial cells lining the respiratory tract, by reducing
lipopolysaccharides-induced acute lung injury(112). These animal studies
suggest that active vitamin D could be effective in reducing the
severity of acute lung injury and suppress a heightened inflammatory
state in COVID-19 patients.