Krüppel-like factor 4 control of immune cell function

Abstract

Krüppel-like factor 4 (KLF4) belongs to a family of transcription factors that contain conserved zinc finger DNA binding domains, including specificity proteins (SPs) and Krüppel-like factors (KLFs). KLF4 plays a vital role in regulating cellular differentiation, proliferation and adaptation to a broad spectrum of internal and external cues. In the context of the immunity, KLF4 is appreciated as critical to both the innate and adaptive arms of the immune system. The current review article focuses on these aspects of KLF4 action as well as implications of this work for impacting human health.

Keywords: KLF4; SP family; homeostasis; immune cells; innate & adaptive immune response.

Figure 1

Interaction of KLF4 with innate and adaptive immune cells. KLF4 plays a crucial role in regulating the differentiation and function of various immune cells. In an innate immunity context, KLF4 promotes anti-inflammatory responses influencing tissue repair and immune resolution. In an adaptive immunity context, KLF4 is involved in immune modulation, specifically impacting activation, proliferation, and cytokine production to maintain immune homeostasis.

Figure 2

KLF4 mechanistically modulates monocyte differentiation and macrophage populations and polarizations. It cooperates with PU.1 to promote monocyte differentiation while upregulating CD14, a key monocyte marker. In macrophages, KLF4 inhibits NF-κB signalling, reducing proinflammatory M1 polarization, while enhancing Stat6/IL-4 signalling to drive M2 macrophage polarization, facilitating tissue repair and anti-inflammatory responses.

Figure 3

KLF4 inhibits neutrophil activation of proinflammatory response. Via the suppression of NF-κB pathway, nuclear translocation and subsequent transcription of proinflammatory genes is prevented. Upstream, KLF4 downregulates TLR4 and CD14, reducing neutrophil responsiveness to bacterial LPS and dampening the initiation of inflammatory cascades, thereby limiting excessive inflammation.

Figure 4

KLF4 systematically inhibits lymphocyte maturation. KLF4 systematically inhibits lymphocyte maturation by repressing key regulatory and proliferation factors such as MSC/ABF1 and E47/E12. It downregulates NOTCH1, a critical driver of T cell commitment, and reduces CXCR4 expression, impairing lymphocyte migration and homing. Additionally, KLF4 suppresses anti-apoptotic genes like BCL2 and BCLXL, leading to increased susceptibility to apoptosis and impaired lymphocyte survival.

Figure 5

Bench to bedside applications of KLF4. KLF4 serves as critical therapeutic targets bridging bench to bedside applications in cancer, inflammatory diseases, and metabolic disorders. In cancer, modulating KLF4 expression can influence tumor suppression or progression depending on the context. In inflammatory diseases, KLF4’s role in macrophage polarization and NF-κB inhibition offers potential for controlling chronic inflammation. In metabolic diseases, KLF4 regulates lipid metabolism and insulin sensitivity, presenting a target for metabolic syndrome and diabetes therapeutics.