Table 2 Immune-related miRNAs and their direct target genes expressed in epithelial cells (ECs). MiRNAs directly target the mentioned genes and downregulate their expression and functions

miR-128

M-CSF: A pro-inflammatory cytokine that recruits macrophages to the infection site and promotes them to phagocytose and kill foreign microorganisms [74]

Intestine

[74]

miR-375

KLF5: A member of the KLF family of zinc­ finger transcription factors which acts as a key regulator in a diverse range of important cellular functions in the body [131]. KLF5 is involved in the regulation of several processes such as cell growth, lung development, and cardiovascular apoptosis [131, 132]. It promotes proliferation and suppresses the differentiation of goblet cells [79]

HT-29 cells

[79]

miR-1968-5p

MyD88: A central adaptor for the TLR signaling pathway and an essential modulator of the innate immune response to microbial pathogens which initiates a cascade of signaling events leading to the expression of inflammatory-related genes. It has an important role in maintaining the mutualism between hosts and microbiota in health situations. It plays a key role in the regulation of gut injury [128]

Intestine

[128]

miR-124

TLR6: Toll-like receptors (TLRs) detect invading pathogens and initiate an inflammatory response that subsequently leads to induce specific adaptive immune responses [65]. TLR6, a member of the TLR family, is expressed on the surface of distinct types of immune and non-immune cells

MyD88: Mentioned above

TNF-α: A cytokine that is generated by various cell types, including activated macrophages, T-lymphocytes, natural killer cells, and ECs [65, 133]. It has been known as a crucial regulator of inflammatory responses and can stimulate a series of different inflammatory molecules, thus, this cytokine can be involved in the pathogenesis of several inflammatory and autoimmune diseases [133]

TRAF6: An adaptor protein that acts as a mediator downstream of various receptor signaling with regulatory functions, including members of the TNFR superfamily, the TLR family, tumor growth factor-β receptors, and T cell receptor. Also, TRAF6 can be involved in the activation of other signaling pathways, such as NF-κB, MAPK, PI3K, and interferon regulatory factor (IRF) pathways. This molecule is necessary for the activation of the immune system as well as the maintenance of immune tolerance [134]

STAT3: A transcription factor that is activated downstream of a wide range of cell surface receptors, including cytokine receptors [135, 136]. STAT3 signaling regulates the expression of immune factors and recruits immunosuppressive cells to create a tolerant tumor microenvironment [136]. The activated STAT3 signaling upregulates the expression of oncogenes and plays crucial roles in malignancy, cell proliferation, survival, migration, and immune evasion of many human tumors [136,137,138]. As such, STAT3 plays an important role in the regulation of both T and B cells. Therefore, dysfunction of STAT3 protein in lymphocytes can lead to immunodeficiency as well as autoimmune diseases [135, 136]

IL-6R: Interleukin-6 (IL-6) activates intracellular signaling pathways via a heterodimeric signaling complex consisting of the IL-6 α-receptor (IL-6R) and the signal-transducing β-subunit glycoprotein 130 (gp130). Membrane-bound IL-6R is expressed in a limited number of cell types, including hepatocytes and lymphocytes. This mode of cell activation which IL-6 binds to its membrane-bound receptor is named classic signaling. The IL-6R can be cleaved through proteolysis which leads to the release of soluble IL-6R (sIL-6R) from the cells. The IL-6 binds to the sIL-6R which subsequently can form a signaling complex with gp130 on the cell surface. This complex activates the cells through a mode termed trans-signaling. Principally, all cells of the human body can achieve IL-6 signals by trans-signaling because of the ubiquitous expression of the gp130. Mainly, trans-signaling is causative for pro-inflammatory effects and classic signaling is responsible for anti-inflammatory properties of IL-6 [139, 140]

AHR: A ligand-inducible transcription factor that acts as a component of the host response to environmental stimuli, is essential in the regulation of immune responses and helps to control immune homeostasis. It regulates the differentiation of Th17 and Treg cells. Activation of the intestinal AHR pathway has an anti-inflammatory effect in the gut [71]

A549 cells, BxPC3 cells, Caco-2 cells, HT-29 cells, Colon, Intestine

[65, 71, 137]

miR-19b

SOCS3: SOCS proteins, especially, SOCS1–3 and CISH are involved in the regulation of cytokine receptor signaling. These proteins are negative feedback regulators that are induced directly by STAT proteins and in turn act to negatively regulate the JAK/STAT pathway by various mechanisms. Due to the key roles of cytokines in the immune system, SOCS proteins can influence various aspects of immune cell behavior such as development, activation, differentiation, and polarization. They are also implicated in a range of immune-related diseases [141]. SOCS3 acts as a key regulator of immunity and inflammation via negative regulation of multiple cytokine signaling pathways such as the IL-6 family members [141, 142]

Intestine

[142]

miR-682

PTEN: Generally is known to repress cell survival signaling, such as Akt, and therefore promotes cell death [143]

Intestine

[143]

miR-192

MIP-2α (CXCL2): A chemotactic CXC chemokine that is expressed by ECs and macrophages. It is significantly elevated in ulcerative colitis tissues [67]

Colon

[67]

miR-92b

Sirt6: A nicotinamide adenine dinucleotide-dependent enzyme which acts as a protective molecule. It plays roles in metabolism, aging, and disease and protects intestinal ECs against inflammatory injury [144]

Intestine

[144]

miR-346

VDR: A nuclear hormone receptor that mediates the biological activities of the vitamin D hormone. Epithelial VDR signaling plays a key role in maintaining the integrity of the mucosal epithelial barrier and protects against mucosal inflammation [145]

Colon, Intestine

[145]

miR-541-5p

HMGB1: A highly conserved nuclear protein that has a role in inflammatory progression. It is considered a putative danger signal for various inflammatory diseases. It plays a critical role in the pathogenesis of acute lung injury [146]

Alveolus

[146]

miR-145-5p

KIF3A: A member of the kinesin-2 family and a component of a trimeric motor complex that regulates microtubular function and transport. This complex is required for the formation and function of motile, non-motile, and sensory cilia. KIF3A plays important roles in respiratory ECs, such as barrier function, epithelial repair, and intracellular protein trafficking. Deficiency of KIF3A in respiratory ECs implicates in a high susceptibility to aeroallergens and airway hyperresponsiveness, and increases the severity of pulmonary eosinophilic inflammation and Th2-mediated inflammation following aeroallergen exposure. The human KIF3A gene locus is associated with susceptibility to atopic dermatitis, rhinitis, and asthma [18, 147]

Airway

[18]

miR-30c-5p

SOCS1: A member of the SOCS family proteins that is induced by a wide range of cytokines and known as a negative feedback inhibitor of the JAK/STAT signaling pathway induced by cytokines [148]. SOCS1 regulates various cytokines involved in the control of immunity and inflammation. For instance, it is one of the inducible negative regulators of IFN signaling [141, 148]

JAK1: The JAK/STAT pathway is utilized by the majority of cytokine receptors to transmit signals into the nucleus for the regulation of specific genes. In mammals, the JAK family consists of 4 members (JAK1, JAK2, JAK3, and TYK2) [141]. JAK1 is widely expressed in almost all tissues and is involved in various cytokine-receptor signaling, such as IL-2R, -4R, and -6R [149]. Also, JAK1 is a key signaling component in IFN-I signaling [149, 150]

Vero E6 cells, MARC-145 cells

[148, 150]