Leptin in the Respiratory Tract: Is There a Role in SARS-CoV-2 Infection?

Abstract

Leptin is a pleiotropic adipocytokine involved in several physiologic functions, with a known role in innate and adaptive immunity as well as in tissue homeostasis. Long- and short-isoforms of leptin receptors are widely expressed in many peripheral tissues and organs, such as the respiratory tract. Similar to leptin, microbiota affects the immune system and may interfere with lung health through the bidirectional crosstalk called the "gut-lung axis." Obesity leads to impaired protective immunity and altered susceptibility to pulmonary infections, as those by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although it is known that leptin and microbiota link metabolism and lung health, their role within the SARS-CoV2 coronavirus disease 2019 (COVID-19) deserves further investigations. This review aimed to summarize the available evidence about: (i) the role of leptin in immune modulation; (ii) the role of gut microbiota within the gut-lung axis in modulating leptin sensitivity; and (iii) the role of leptin in the pathophysiology of COVID-19.

Keywords: SARS-CoV-2; immunity; leptin; microbiota; obesity.

FIGURE 1

(A) Leptin history in the respiratory tract. Since its discovery 27 years ago, the adipocytokine leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ, also on respiratory tract. Leptin was discovered in mouse by Friedman group (Zhang et al., 1994) and soon leptin receptor (ObR) expression was found in the lung from rat (Wang et al., 1996). In 1997, it was studied as the correlation between serum leptin and lung cancer cachexia (Simons et al., 1997) and in 1998, the cross-talk between human lung and adipose tissue started to be identified (Kielar et al., 1998; Tankersley et al., 1998). Since 1999, leptin and its receptor are studied in patients with chronic obstructive pulmonary disease (COPD), asthma (Heuck and Wolthers, 1999; Takabatake et al., 1999; Bruno et al., 2005a,2009), and since 2006 also in patients with allergic rhinitis (Unal et al., 2006; Bruno et al., 2019). With coronavirus disease 2019 (COVID-19) pandemic, it has been hypothesized a role of leptin in severity disease (Guglielmi et al., 2021; Wang et al., 2021). (B) Leptin and the gut-lung axis. Both leptin and microbiota influence innate and adaptive immune system and are critical for maintaining homeostasis of the immune system in the lungs (iBALT = inducible bronchus-associated lymphoid tissue) and in the gut (GALT = gut-associated lymphoid tissue). High fiber diet can increase the prevalence of Bacteroidetes species as well as the production of short chain fatty acids (SCFAs), which maintain the health immune system through the induction of regulatory T cells (Tregs) and interleukin-10 (IL-10) production and by inhibiting inflammation. On the other hand, high fat diet can increase both adipose tissue and Firmicutes species, associated with dysbiosis, inflammation, and with increased of effector T cells and IL-17 and tumor necrosis factor-α (TNF-α) production as well as the level of circulating leptin. This latter is also increased by dysbiosis. In turn, lung disorders and respiratory infections boots dysbiosis.

FIGURE 2

Role of leptin in increasing the severity of COVID-19 in obese subjects. The altered expression of leptin/leptin receptor pathway and the increase of leptin resistance in obese subjects, together with the alteration of microbiota, induces inflammation, and impairs the function of the immune system. In this context, leptin and dysbiosis could be key factors associated with increased severity of COVID-19 in obese subjects.