A recent study has uncovered a cellular mechanism that helps prevent immune responses from turning into excessive inflammation that could lead to tissue damage, after researchers found that an enzyme called TRIM13 protects immune cells from stress inside the endoplasmic reticulum and regulates calcium flow within it.

The endoplasmic reticulum is an essential part of the cell, responsible for manufacturing proteins destined for secretion or incorporation into cell membranes, as well as modifying these proteins and folding them into their correct shape before transport to their final destination.

But when protein production outpaces the endoplasmic reticulum's capacity to handle them, unfolded or misfolded proteins begin to accumulate, prompting the cell to activate a defense system known as the unfolded protein response to restore balance and prevent damage.

Cells rely on another system called endoplasmic reticulum-associated degradation to identify defective proteins and transport them for disposal before their accumulation disrupts cell function.

In the study published in the journal Science Signaling, researchers found that the enzyme TRIM13, which operates within this system, plays an important role in suppressing inflammation resulting from activation of macrophages, immune cells that engulf microbes and damaged cells and release inflammatory molecules to fight infection.

The researchers focused on an immune receptor called TLR4 found on the surface of macrophages, which detects a component present on the outer surface of certain bacteria.

Activation of this receptor triggers an inflammatory response necessary to fight infection, but it can become harmful if prolonged or excessive.

Experiments on macrophages taken from mice showed that the enzyme TRIM13 targets a protein called STIM1, located on the endoplasmic reticulum, which acts as a sensor for calcium levels inside it.

When calcium stored inside the reticulum decreases, STIM1 helps open channels in the cell membrane that allow more calcium ions to enter from outside, and these ions play a key role in regulating multiple cellular processes, including activation of immune cells and production of inflammatory substances.

However, researchers found that TRIM13 determines the amount of STIM1 inside cells by targeting it for endoplasmic reticulum-associated degradation, preventing excessive calcium entry and maintaining endoplasmic reticulum stability.

In cells lacking TRIM13, higher levels of STIM1 accumulated and more calcium entered the cells, leading to increased endoplasmic reticulum stress and activation of one branch of the unfolded protein response, which depends on a protein called IRE1α.

This protein normally helps cells adapt to endoplasmic reticulum stress, but its excessive or chronic activation can promote the production of inflammatory signals and exacerbate tissue damage.

To test the importance of this mechanism in the body, researchers used a mouse model of colitis based on inflammation resulting from TLR4 activation, and results showed that deleting TRIM13 from macrophages worsened intestinal inflammation and increased disease severity, indicating that the enzyme acts as a brake to prevent the immune system from sustaining a destructive inflammatory response.

In an additional experiment, researchers treated mice lacking TRIM13 with an inhibitor of IRE1α and observed that the treatment alleviated intestinal inflammation, despite the continued absence of the enzyme.

This result indicates that increased IRE1α activity is a key link connecting disrupted calcium flow, endoplasmic reticulum stress, and exacerbated inflammation.

The researchers said that the study shows TRIM13 not only functions as part of the system for disposing of defective proteins, but also plays a role in regulating the immune response by controlling STIM1 levels and calcium balance within cells.

They added that the findings may help understand the mechanisms behind some inflammatory bowel diseases and other conditions where chronic inflammation is linked to endoplasmic reticulum stress and disrupted calcium signaling.

Targeting the STIM1-IRE1α pathway may in the future enable the development of treatments that reduce excessive inflammation without completely disabling the immune system's ability to fight infection.

However, the results are based on laboratory experiments and animal models, and further studies are still needed to determine whether the same mechanism operates in humans, as well as the safety and efficacy of inhibiting IRE1α in treating inflammation.